The administration by inhalation enables the dose to be delivered directly to the airways. By this route of adminstration, it is possible to give a small dose and thereby minimizing unwanted side-effects. The drawbacks of the current available bronchodilators are their relatively short duration of action. Studies with formoterol given by inhalation have shown its much longer duration than any other bronchodilators on the market. By using a compound with long duration it would be possible to avoid the nocturnal asthma, so often causing considerable anxiety and debility to the patients. Formoterol gives less nocturnal waking. Formoterol has been registered for oral adminstration in Japan since 1986.
Formoterol has two asymmetric carbon atoms in the molecule. It is used as the fumarate salt of one of the two possible pairs of enantiomers of 3-formamido-4-hydroxy-.alpha.-[N[1-methyl-2-(p-methoxyphenyl)ethyl]aminome thyl]benzyl alcohol. Formoterol consists of the enantiomers, which have the RR+SS configuration.
Formoterol was first described in a Japanese patent application (Yamanouchi Pharmaceutical, Japan no 13121, priority 5 Feb. 1972, related priorities Japan no 39416 (19 Apr. 1972), 51013 (23 May 1972) and 52925 (27 May 1972)). The corresponding patent in Germany is DE 2 305 092.
DE 2 366 625 discloses some .alpha.-aminomethylbenzyl alcohol derivatives which are intermediates for preparing end products useful as bronchodilators. Example 3 therein refers to the preparation of 3-formamido-4-hydroxy-.alpha.-(N-benzyl-N-isopropylaminomethyl)benzylalcoh ol.
The hitherto published synthetic routes to formoterol involve a nucleophilic substitution reaction of an amine to a bromoketone according to: ##STR1## The reduction of the nitrogroup is accomplished by either Fe/HCl or Sn/HCl followed by formylation with a mixture of formic acid and acetic anhydride. The presence of acetic anhydride has shown to give some undesired acetylated products. The separation step of the two pairs of enantiomers are tedious and several recrystallizations are needed to obtain sufficient purity of the product.
The patent application J 50012-040 (priority date 31 May 1973) discloses a process where a substituted ketone is undergoing a reductive alkylation with the appropriate amine.
ES 2 005 492 (S. A. Lasa Laboratorios) describes a process for the synthesis of formoterol characterized by a coupling reaction between 3-formamido-4-benzyloxyphenyloxirane and the unprotected 2-(4-methoxyphenyl)-1 -methylethyl amine and is followed by tedious and troublesome steps (use of crown ethers, hydrofluoric acid, solvents like benzene and methylene chloride causing environmental and health problems, HCOOH/acetic anhydride etc.) to the final product.
The synthesis of formoterol and closely related compounds have also been reported in Chem. Pharm. Bull., 25(6), 1368-1377 (1977), where 3-nitro-4-benzyloxy-.alpha.-(N-substituted aminomethyl)benzyl alcohols are used as the keyintermediate. Use of Raney-nickel for the reduction of the nitro group has been rejected due to difficulties in obtaining pure products without a chromatographic step. However, the general procedure for the preparation of 3-amino-4-benzyloxy-.alpha.-(N-substituted aminomethyl)benzyl alcohols reported on page 1373 of said document involves a tedious and cumbersome column chromatographic step on silica gel using benzene-ethyl acetate as the eluent.
There is a strong desire of synthesizing formoterol fumarate (as dihydrate) by a simple procedure causing small environmental concerns e.g. by elimination of solvents like benzene.